The ?-herpes virus murine cytomegalovirus (MCMV), a homologue of human CMV, is a well-characterized animal model of viral infection that results in a non-replicative, chronic infection of an immune-competent animal. MCMV is cleared within days from the spleen and the liver, but persists in the salivary glands for several weeks. NK cells are crucial for the early containment of MCMV in the spleen before T cells can mount a targeted effector response. Our preliminary data show that the spleen harbors mostly classical NK cells, while the liver and the salivary glands harbor two distinct subsets of NK cells. In prior work, we have shown that the salivary gland NK cells are hyporesponsive, possibly explaining the MCMV persistence in this organ. Our new preliminary data show that salivary gland NK cells regain normal effector functions against MCMV when adoptively transferred into different tissue environments. Therefore, our data suggest that the salivary gland microenvironment regulates NK cells and/or NK-like cells by calibrating their threshold of activity. Here we propose experiments designed to reveal the underlying mechanisms leading to MCMV persistence. We will target NK cells at the receptor level and during subsequent downstream signaling. By using both a genetic and biochemical approach, we will attempt to modulate their effector functions. In Specific Aim 1, using mice with targeted mutations for SHP-1 and SHP-2, we will determine the nature of the NK cell response to MCMV. In Specific Aim 2, we test the impact of cadherin/KLRG1 interaction. In Specific Aim 3, we will determine the respective contribution of salivary gland E4BP4- dependent and E4BP4-independent NK cells during MCMV infection. The findings generated from the proposed work could potentially lead to the development of drugs that reverse CMV persistence.